We are proposing research aimed at clarifying biochemical mechanisms involved in the development of pulmonary edema due to increased lung vascular permeability. We have completed work in an unanesthetized sheep lung lymph preparation showing that lung lymph flow and protein content are sensitive indexes of filtration from lung vessels and that Pseudomonas bacteremia is predictably followed by a long period of steady state increased lung vascular permeability. In the same sheep preparation, we will identify potential mediators of permeability increase by comparing the effects of histamin, serotonin, prostaglandins, prostaglandin synthetase inhibitors, xanthines and catecholamines on lung lymph flow and protein content with the effects of increased pressure on these variables in the same animals. We will test the ability of antagonists of possible mediators and of agents which may prevent endogenous mediator release to prevent and reverse the permeability change caused by Pseudomonas, and we will measure release, clearance and metabolism of prostaglandins by the lung under normal and abnormal conditions. Based on all of these data, we will formulate hypotheses describing the biochemical events involved in the development of increased lung vascular permeablity and suggest possible approaches to therapy of the lesion.